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hERG and its Evaluation in Drug Development

2021-09-23
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Drug safety evaluation plays an extremely important role in the drug development process. As some non-cardiovascular drugs have been found to induce acquired QT prolonged syndrome (LQTS), leading to severe arrhythmia (Torsade de Pointes) , TdP) and after withdrawing from the market, the safety evaluation of the drug on the heart becomes extremely important. The QT interval of the heart refers to the period from the beginning of the QRS complex to the end of the T wave, including the process of ventricular depolarization and repolarization. QT interval extension is receiving more and more attention and is considered a new drug One of the key indicators of safety evaluation.
In cardiomyocytes, the potassium channel encoded by hERG (human Ether-a-go-go Related Gene) mediates a delayed rectifier potassium current (IKr), and IKr inhibition is the most important mechanism by which drugs cause QT interval prolongation. Because of its special molecular structure (Figure 1), the loss of its function or drug inhibition of hERG will affect the repolarization process of the cardiac action potential and cause the QT interval to be prolonged. At the same time, it may induce torsade de pointes ventricular tachycardia, leading to heart rhythm. Abnormal.

As the target of anti-arrhythmic drug therapy, hERG potassium channel is increasingly reflected in the safety testing of new drugs and the development of new drugs. At present, detecting the effect of compounds on hERG potassium channels is a key step in preclinical evaluation of the cardiac safety of compounds, and it is also the necessary information for new drug approval required by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA). , In order to avoid the risk of drug cardiotoxicity. It is estimated that every 10% increase in the prediction rate of drug-induced arrhythmia can save US$100 million in development costs for each drug in the drug development process. The hERG potassium channel plays such an important guiding role in drug development. Next, this article briefly introduces the relevant knowledge of hERG inhibition.

Evaluation Technology for hERG Inhibition

With the continuous deepening of research, the safety evaluation technology of hERG inhibition has become more mature. At present, there are many mature evaluation methods on the market, such as Automated Patch-Clamp technology (Automated Patch-Clamp), traditional patch-clamp technology ( Conventional Patch-Clamp) and FluxORTM Thallium Assay.

Fully automatic patch clamp technology (hERG Qpatch assay): The traditional patch clamp technology is adsorbed on the cell surface through a special glass tube to form a high-impedance gigaohm seal, which can accurately record the changes in the current mediated by the ion channel. It is the “gold standard” for the study of ion channels, but it has high technical requirements for operators and low throughput, which cannot meet the current large demand for hERG toxicity evaluation in drug research and development.

Traditional patch-clamp technique (hERG manual patch-clamp asssay): The patch-clamp technique (Conventional Patch-Clamp) is the most important technical means for studying ion channels, and is recognized as the “gold standard” for ion channel research, and is the most accurate The experimental method of measuring ion channels is suitable for studying the mechanism of interaction between compounds and ion channels, and can also be used for the toxicity evaluation of candidate drugs and the structure optimization of lead compounds in the process of new drug application.

FluxORTM Thallium Assay: Thallium assay uses FluxORTM fluorescent dyes to test the effect of compounds on hERG potassium channels. The thallium-sensitive fluorescent dye is loaded into the cell membrane, and the thallium ions outside the cell enter the cell along the concentration gradient through the open hERG potassium ion channel, and then combine with the fluorescent dye to produce fluorescence. FluxORTM thallium assay has been widely used internationally by pharmaceutical companies and scientific research institutions for the detection of compound hERG activity, because it can be tested on 96-well plates or 384-well plates to meet high-throughput requirements, and is suitable for preliminary compound screening and piloting. Compound optimization.

With advanced drug cardiotoxicity evaluation equipment and strong experimental data for endorsement, it not only reduces the risk of drug research and development, but also greatly promotes the process of drug research and development. Of course, it also provides a certain guarantee for patients to use safer and more effective drugs.

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